Jean Gosselin

Differential interleukin-2 and interferon-γ production by human lymphocyte cultures exceptionally resistant to Epstein-Barr virus immortalization

Epstein-Barr virus (EBV) readily immortalizes human peripheral blood lymphocytes (PBL) in vitro. However, during the past several years, we found that PBL from two exceptional EBV-seropositive healthy adult individuals were refractory to immortalization by EBV. We report here a study aimed at learning about the immunobiological features which differentiate these EBV-resistant (R) PBL from others which are susceptible (S) to EBV immortalization. Results of this investigation indicate that: (a) Following EBV infection, R-PBL produced significantly higher amounts of interferon gamma (IFN-gamma) than S-PBL. There were however no differences in regard to interferon alpha production between these two types (R and S) of EBV-infected cultures. (b) R-PBL had a maximal interleukin-2 (IL-2) production by S-PBL occurred at least 48 hr later, i.e., at Day 7. (c) The percentage of non-B cells expressing the IL-2 receptor was also higher in EBV-infected R-PBL than S-PBL. (d) In contrast, expression of IL-2 receptors after EBV infection was higher on B cells from S-PBL than on B cells from R-PBL. Interestingly, no differences were noted in regard to IL-2 receptor expression between R-PBL and S-PBL treated with mitogens (i.e., phytohemagglutinin and pokeweed mitogen). (e) Finally, using anti-IL-2 and anti-IFN-gamma antibodies in EBV-infected R-PBL cultures, we were able to obtain EBV-induced immortalization of these cultures. Taken together, these results suggest that an early IL-2 synthesis and high IFN-gamma production by EBV-infected PBL play an important role against lymphocyte immortalization by EBV.

Tac expression induced by Epstein — Barr virus is restricted on non-transformable B lymphocytes

During the course of a comparative study dealing with the immortalization of lymphocytes from a large number of normal healthy donors, we found that B cells of two of these individuals could not be immortalized by Epstein-Barr virus (EBV) under the standard conditions. The expression of the Tac antigen on the membrane of EBV-infected B cells from these two donors was compared with that of B cells from EBV immortalization-susceptible ones. The method used was two-colour immunofluorescence cytofluorometer analysis. We found that the Tac antigen expression was significantly and repeatedly reduced in the case of the two immortalization-resistant donors. This difference might be related to a genetic control of the resistance to EBV-immortalization.

Epstein-Barr Virus Infection and Monokine Synthesis

Epstein-Barr virus (EBV) is a human lymphotropic herpes-virus that causes infectious mononucleosis; virus may also have an etiological role in nasopharyngeal carcinoma and Burkitt’s lymphoma. EBV also transforms and immortalizes human B lymphocytes “in vitro”. EBV infection leads to the production of virus-neutralizing antibodies (1), to an increase of natural killer cell (NK) activity (2–3) and to T cell-mediated cytotoxicity (4–5). These immune responses are regulated in part by various cytokines such as interleukin-2 (IL-2) (6-8) and gamma interferon (IFNγ) (6-7,9). However, little is known about the induction of cytokine synthesis by EBV. Recent studies show that EBV can induce IL-1, IL-2 and IFN synthesis “in vitro” (10). We have also reported that resistance of certain lymphocyte cultures to EBV immortalization is associated with a strong production of IL-2 and IFNγ (11). Moreover, we have recently shown that EBV can also interact with cells of the monocytic lineage and inhibit TNF a synthesis without interfering with IL-1 production (12).

Epstein-Barr Virus Infection and Immunoregulation

The Epstein-Barr virus (EBV) is a well-known example of a human virus which interacts most intimately with the immune system. EBV is a polyclonal B lymphocyte activator, can immortalize B cells and, depending on situations, can also induce different T cell and cytokine activities (1–6). The present paper examines briefly several immunoregulatory aspects of EBV interaction with the immune system, many of which are pertinent to our understanding of immune controls over EBV infections. Various effects of EBV infection on cells of the immune system and their products are thus examined.